In 535, as part of his administrative reforms, Justinian I abolished the diocese,[dubious– discuss] and the comes Orientis became the provincial governor of Syria I, while retaining his previous rank of vir spectabilis and his salary.[3]

The entire area of the former diocese came under Sassanid Persian occupation in the 610s and 620s, during the Byzantine–Sassanid War of 602–628. Shortly after the Byzantine victory in the war and the recovery of the region, it was again lost, this time permanently, to the Muslim conquests: by the 640s, Cilicia formed the border between Byzantium and the new Arab Caliphate, while Cyprus became a disputed territory. From the old provinces of the Diocese of the East, only Isauria and parts of the two Cilicias remained under Byzantine rule, grouped under the new Anatolic Theme.[2]